Process for preparing (±)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine

ABSTRACT

The present invention relates to a process for preparing (±)-trans-4-p-fluorophenyl-3-hyroxymethyl-1-methylpiperdine of formula (I). The present invention also relates to novel intermediates of the formula (IX) and (IX′) methods for preparing said intermediates and the use of said compounds for preparing Paroxetine and Omiloxetine.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/EP01/00049 which has an Internationalfiling date of Jan. 4, 2001, which designated the United States ofAmerica.

The present invention relates to a process for preparing(±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine of formulaI:

The compound of formula I is a key precursor in the synthesis of(−)-trans-4-p-fluorophenyl-3-(3′,4′-methylenedioxyphenoxymethyl)-piperidine, a compound also known as paroxetine(WHO—INN), of formula II, as well as(−)-trans-N-p-flourobenzoylmethyl-4-(p-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperdine,a compound also known as omiloxetine (WHO—INN), of formula III. Thesecompounds inhibit 5-hydroxytryptamine (5-HT) reuptake and are useful asantidepressants.

U.S. Pat. No. 3,912,743 describes for the first time the compounds ofgeneral formula A:

wherein, among others, Y is halogen, R₁ is an optionally substitutedphenyl group and R₂ is hydrogen or alkyl. The preparation of compound Adisclosed in U.S. Pat. No. 3,912,743 and subsequently in U.S. Pat. No.4,007,196 is based on a Grignard reaction in which arecoline and4-flourophenylmagnesium bromide are reacted. This procedure has thedisadvantage that arecoline is a very irritant and expensive product.Moreover, the 1,4-addition of the Grignard reagent competes with the1,2-addition. This leads to product mixtures and thus involves complexpurification steps and results in low reaction yields. Furthermore, theimmediate precursor of compound A is obtained as a mixture of cis-formand trans-form isomers. All of this hinders the industrial applicationof the procedure.

U.S. Pat. No. 4,902,801 discloses the preparation of compounds ofgeneral formula A by reducing 4-aryl-2,6-dioxo-3-piperidincarboxylicacid esters of general formula B:

wherein, among others, Y is halogen, R₁ is alkyl and R₂ is alkyl.Compound B with Y=p-F and R₂═Me would lead to intermediate I. Thisintermediate can be synthesized by reaction of N-methyl amidomalonicacid esters with cinnamic acid esters. Cinnamic acid esters are formedonly in low yields and thus the resulting process is very expensive.Other patents describe the production of intermediate B by addition ofmalonic acid esters to methylcyanamide (EP 374,675). According to thisvariant, free methylamine has to be used and, consequently, specialequipment is needed. All of this leads to high manufacturing costs ofboth variants.

Compound I can also be prepared by reducingtrans-4-flouropenyl-6-oxopiperidin-3-carboxylic acid esters (compoundC), wherein R₁ is alkyl (EP 802,185, ES 96/00,369, EP 812,827 and WO98/53,824) and subsequent N-methylation (EP 802,185) or by methylationof compound C and subsequent reduction (WO 98/53,824).

Compound C is prepared by adding cyanoacetic acid ester to cinnamic acidester in the presence of a base followed by reduction and simultaneouscyclization of the resulting 2-cyano-3-arylglutaric derivative. If thereduction of the nitrile is carried out by hydrogenation, elevatedhydrogen pressures may be needed (EP 812,827), which involves evidentrisk of defluoration or the use of platinum oxide as a catalyst, whichincreases the synthesis costs. The reductive cyclization (EP 802,185, EP812,827, WO 98/53,824) generally yields cis-trans mixtures.Consequently, the undesired cis compound has to be separated byfractional crystallization or employment of a further isomerizationstep.

Similarly, compound D, wherein R₁ is alkyl, may also be a precursor ofintermediate I (CA 131: 184870 and WO 00/26,187).

Also in the synthesis of this compound, vigorous conditions are neededfor the reduction of the nitrile group.

In another method intermediate I is prepared by reducing1-methyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropiperidine. The formationof this compound involves a reaction between methylamine, formaldehydeand α-stirene (U.S. Pat. No. 4,007,196 and WO 96/36,636). The difficultyof working with methylamine and above all the neurotoxicity of4-aryl-1-alkyl-1,4,5,6-tetrahydropiperidine derivatives make thisprocedure unsafe and industrially non-applicable.

According to the background of this invention, it is desirable toprovide an alternative method for the production of intermediate I,wherein said compound is preferably obtained as trans isomer directly.This would better meet the requirements for the costs, safety andecology of the production of pharmaceutically active substances, such asparoxetine or omiloxetine.

The process of the present invention for preparing(±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine isillustrated in the following reaction scheme:

In a first step p-fluoroacetophenone V, a commercially availableproduct, is condensed with a unit of formaldehyde (paraformaldehyde oraqueous formaldehyde) and a unit of methylbenzylamine through Mannichreaction. The reaction is generally carried out in a polar solvent(alcoholic or aqueous). The methylbenzylamine can be employed in form ofits addition salts with strong inorganic or organic acids. Examples ofsuitable physiologically tolerated organic and inorganic acids arehydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid or benzoic acid. Other acids which can be used are describedin Fortschritte der Arzneimittelforschung, volume 10, pages 224 et seq.,Birkhäuser Verlag, Basle and Stuttgart, 1966. If the methylbenzylamineis used in form of a salt, eg. as hydrochloride, then compound VI isalso isolated as a salt, eg. the hydrochloride, which has the form of awhite crystalline solid.

In a second step the benzyl group is unprotected from amine VI. Theremoval of the benzyl group is preferably carried out with a reducingagent that essentially does neither lead to a defluorination of thefluorophenyl group nor a reduction of the carbonyl group. Suitablereducing agents comprise hydrogen in the presence of a homogeneous orheterogeneous catalyst, preferably Raney nickel or palladium on carbon(Pd/C).

Further, the removal of the benzyl group is preferably carried out in amedium containing water or at least one alcohol or a mixture comprisingat least one alcohol and water. The latter medium is the mostappropriate to achieve a better conversion and to minimize the reductionof the carbonyl group of compound VI to an alcohol group. If analcoholic reaction medium or a medium containing at least one alcohol isemployed, the alcohol is preferably selected from C₁-C₄-alcanols, eg.methanol, ethanol, n-propanol, isopropanol, n-butanol, and mixturesthereof. Particular preference is given to mixtures of water andmethanol. In this manner, reductions may be accomplished at an earlierstage with outstanding yield and purity.

It is convenient to isolate compound VII in the form of an addition saltas defined above, eg. as hydrochloride and liberate it in situ in thefollowing reaction step, wherein compound VII is reacted with an alkyl3-halo-3-oxopropionate (VII′). If compound VII is employed in form of anaddition salt then the reaction with compound VII′ affords two baseequivalents, one for liberating the amine from the starting salt, eg.the hydrochloride, and the other for neutralizing the formed HCl. Incompound VII′ alkyl preferably is C₁-C₄-alkyl, especially methyl. 3-halopreferably is 3-chloro. It is not advisable that the basic medium isaqueous because then the acid chloride VII′ might be hydrolyzed.Preferably, the reaction medium comprises at least one organic solventselected from aromatic hydrocarbons, eg. benzene, toluene and xylene,chlorohydrocarbons, eg. CH₂Cl₂, CHCl₃, CCl₄, C₂H₄Cl₂, and mixturesthereof. The employed base is preferably selected from tertiary amines,eg. triethyl amine.

The intramolecular Knoevenagel condensation of compound VIII isthermodynamically favoured because a highly conjugated cyclic compoundis formed.

It has been found that in a basic medium containing nitrogenous bases(pyridine, piperidine and the like), the reaction does not occur with anappropriate yield. A convenient conversion is accomplished in thepresence of ammonium acetate-acetic acid or in a basic medium comprisingan alkoxide. Compound IX easily crystallizes from such a reaction mediumand may be isolated with high purity and yield.

Depending on the reaction conditions compound IX or a mixture with itspositional isomer IX′ is obtained

It is an object of the present invention to provide new compounds VI,VII and VIII as well as methods for preparing said compounds. Theinvention also embraces the acid addition salts of the compounds offormulae VI and VII with inorganic or organic acids. It is also anobject of the present invention to provide new compounds IX and IX′ inthe form of the pure isomers or mixed in any proportion.

Finally, compounds IX and IX′ may be reduced by using differenthydrides, such as sodium hydride, potassium hydride, magnesium hydride,calcium hydride, sodium boron hydride, potassium boron hydride, lithiumboron hydride, lithium aluminium hydride, sodium aluminium hydride,aluminium hydride, sodium hydride and bis(2-methoxyethoxy)aluminium,aluminium hydride mono(C₁₋₄ alkoxy)aluminium, lithium aluminium di(C₁₋₄alkoxy)aluminium, sodium hydride and diethylaluminium or the mixtures ofany of them. Particularly advantageous is lithium aluminium hydride inthe presence or in the absence of an inorganic salt. The reduction maybe accomplished using a borane or diborane as well. The reaction may becarried out in different low-polarity solvents, such as tetrahydrofuran(THF), ethyl ether, tert-butylmethyl ether, mixtures of toluene or analkane, in particular a C₆-C₉-alkane (heptane, octane and the like) or acycloalkane, in particular a C₅-C₈-cycloalkane (cyclohexane,cycloheptane and the like) and THF and the like, THF being preferred.

The process of the present invention has the advantage over processes ofthe prior art that three functional groups are simultaneously reduced ina single reaction step and the reduced agent is obtained only in thetrans form.

Consequently, in this manner, and in contrast to most known processes,further epimerization steps are avoided.

According to a preferred embodiment, the invention is directed to aprocess for preparing(±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine of formula

comprising

-   -   i) reacting p-fluoroacetophenone with formaldehyde and        methylbenzylamine or an addition salt thereof with at least one        inorganic or organic acid to obtain a compound of formula VI    -    or an addition salt thereof with at least one inorganic or        organic acid,    -   ii) hydrogenating of the compound of formula VI or the addition        salt thereof to obtain a compound of the formula VII    -    or an addition salt thereof,    -   iii) reacting the compound of formula VII or the addition salt        thereof with an alkyl 3-halo-3-oxopropionate of the general        formula VII′        XCOCH₂COOR  VII′    -    wherein X is halogen, in particular chlorine or bromine, and R        is an alkyl group having 1 to 4 carbon atoms to obtain a        compound of formula VIII,    -    wherein R is defined as above,    -   iv) performing an intramolecular condensation of the compound of        formula VIII to obtain a compound of formula IX or IX′    -    wherein R is an alkyl group having 1 to 4 carbon atoms, or a        mixture thereof, and    -   v) reducing the compound(s) IX and/or IX′ to obtain the compound        of formula I.

Further embodiments of the invention refer to processes for preparingcompounds of the formula I, characterised by one of the followingsequences of the above reaction steps: ii) to v); iii) to v); and iv) tov). Compound I is a key precursor in the synthesis of paroxetine andomiloxetine. U.S. Pat. No. 4,902,801 describes how the racemic mixture((±)-trans) may be resolved into the enantiomer (−)-trans of formula IVusing (−)-di-p-toluoyltartaric acid.

U.S. Pat. No. 4,007,196 provides a process for the preparation ofparoxetine acetate from(−)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methyl piperidine offormula IV. Spanish Patent 2,117,557 provides a process for thepreparation of omiloxetine from paroxetine acetate.

The present invention is further illustrated by the subsequentnon-limiting examples.

EXAMPLE 1 3-(benzyl-methylamino)-1-(p-fluorophenyl)-propan-1-onehydrochloride (VI)

A mixture of 114.12 g (0.724 mole) of benzylmethylamine hydrochloride,21.74 g (0.724 mole) of paraformaldehyde, 100 g of p-fluoroacetophenone(0.724 mole) and 7.5 mL of concentrated HCl in 100 mL of ethanol wasrefluxed for 2 hours. Following the addition of another portion ofparaformaldehyde (21.74 g, 0.724 mole), the mixture was refluxed forfurther 2 hours. 75 mL of acetone were added, stirred at 0° C. for 1hour and the solid formed was filtered and washed with acetone. Thesolid (187.6 g, 84%) was pure enough to be used in the following stepwithout prior purification.

M.p.=164-165° C.

IR (KBr), cm⁻¹: 3436, 3062, 2895, 2629, 2550, 1682, 1599, 1508, 1370,1236, 741, 699.

¹H NMR (CDCl₃), δ (ppm): 8.03 m, 2H, aromatic; 7.64 m, 2H, aromatic;7.46 m, 3H, aromatic; 7.14 m, 2H, aromatic; 4.42-4.08 m, 2H, COCH ₂;3.83 q, J=7.2 Hz, 2H, CH ₂Ph; 3.68-3.33 m, 2H, CH ₂N; 2.70 s, 3H, CH ₃.

¹³C NMR (CD₃OD), δ (ppm): 196.2 CO; 167.2 d, J=253.1 Hz, Car-F; 133.7 d,J=2.3 Hz, Car in para position to F; 132.14 CHar benzyl in orthoposition; 132.13 d, J=10.3 Hz, CHar in meta position to F; 131.0 CHarbenzyl in para position; 130.7 Car benzyl; 130.2 CHar benzyl in metaposition; 116.6 d, J=22.9 Hz, CHar in ortho position to F; 61.4 CH₂Ph;52.2 CH₂N; 40.6 CH₃; 34.2 COCH₂.

EXAMPLE 2 1-(p-fluorophenyl)-3-methylamino-propan-1-one hydrochloride(VII)

To a solution of 42.15 g (0.137 mole) of compound VI dissolved in 221 mLof a MeOH-water (1:1) mixture were added 9.68 g of Pd over 5% carbon(56.5% water). The mixture was hydrogenated at atmospheric pressure for1 hour. The catalyst was filtered and the solvent was evaporated todryness. The solid formed was recrystallized from AcCN and acetone togive 28.6 g (96%) of compound VII as a white crystalline solid.

M.p.=153-154° C.

IR (KBr), cm⁻¹: 3435, 2960, 2770, 2464, 1677, 1690, 1599, 1229, 1160,984, 854, 791.

¹H NMR (CD₃OD), δ (ppm): 8.17-8.07 sc, 2H, aromatic in meta position toF; 7.20-7.31 sc, 2H, aromatic in ortho to F; 3.60 t, J=6.0 Hz, 2H, COCH₂; 3.46 t, J=6.0 Hz, 2H, CH ₂N; 2.82 s, 3H, CH ₃;

¹³CRMN (CD₃OD), δ (ppm): 196.8 CO; 167.1 d, J=254.2 Hz, Car-F; 133.7 d,J=3.4 Hz, Car in para position to F; 132.0 d, J=9.1 Hz, CHar in metaposition to F; 116.6 d, J=21.8 Hz, CHar in ortho position to F; 45.5CH₂N; 35.3 COCH₂; 34.1 CH₃.

EXAMPLE 3 N-[3-(p-fluorophenyl)-3-oxo-propyl]-N-methyl-malonamic acid,methyl ester (VIII, R:CH₃)

46.25 g (0.212 mole) of compound VII were dissolved in 370 mL of CH₂Cl₂and 62.2 mL of Et₃N (45.16 g, 0.446 mole) were added under nitrogenatmosphere. The mixture was taken to 0° C. and 25.85 mL (32.9 g, 0.241mole) of methyl 3-chloro-3-oxopropionate were added for 30 minutes.After stirring at 0° C. for further 30 minutes 70 mL of water wereadded. The organic layer was decanted. The aqueous layer was extractedwith CH₂Cl₂ (2×100 mL). The combined organic layers were washed withwater and the solvent was evaporated in vacuo to dryness to yield 60.4 gof a solid which was recrystallized from MeOH, giving 52.3 g (88%) ofpure compound VIII.

M.p.=80-82° C. IR (KBr), cm⁻¹: 3473, 3068, 3016, 2965, 2920, 1746, 1679,1641, 1601, 1509, 1456, 1433, 1412, 1325, 1252, 1100, 1025, 845, 785.

¹H NMR (CDCl₃), δ (ppm): Mixture of 2 isomers; 8.06-7.95 sc, 2H,aromatic in meta position to F; 7.21-7.08 sc, 2H, aromatic in orthoposition to F; 3.82-3.70 sc, 5H, COOCH ₃+COCH ₂; 3.64+3.46 s+s, 2H, COCH₂CO; 3.29+3.30 t, J=6.6 Hz+t, J=6.6 Hz, 2H, CH ₂N; 3.11+2.98 s+s, 3H, CH₃.

¹³C NMR (CDCl₃), δ (ppm): Mixture of 2 isomers; 196.9+195.3 2CO in paraposition to F; 167.8+167.5+167.2+167.0+165.8+165.6+163.8+; 163.7 2d,Car-F+2NCO+2COOCH_(3;) 132.6+132.4 d, J=3.3 Hz+d, J=3.3 Hz, Car in paraposition to F; 130.4+130.3 d, J=9.9 Hz+d, J=9.9 Hz, CHar in metaposition to F115.6+115.4 d, J=22.0 Hz+d, J=22.0 Hz, CHar in orthoposition to F; 52.2 COOCH₃; 41.2+40.6 CH ₂COOCH₃; 45.3+44.6 CH ₂N;37.2+33.2 N—CH₃; 36.5+36.3 COCH₂.

EXAMPLE 44-(p-fluorophenyl)-1-methyl-2-oxo-1,2,3,6-tetrahydropiridine-3-carboxylicacid, methyl ester (IX, R:CH₃)

To a solution of 50.0 g (0.178 mole) of compound VIII in 90 mL of MeOHwere added 37.4 mL of 21% MeONa (0.133 mole) for 45 minutes at roomtemperature. After stirring for further 2 hours at room temperature, themixture was taken to 0° C. and 7.6 mL of glacial AcOH were added. Thesolid formed was filtered and washed with MeOH, giving 38.7 g (82%) of awhite solid pure enough to be used without prior purification.

M.p.=143-145° C.

IR (KBr), cm⁻¹: 3465, 3076, 3006, 2956, 2837, 1746, 1676, 1638, 1510,1225, 1272, 1026, 843, 805.

¹H NMR (CDCl₃), δ (ppm): 7.44-7.34 sc, 2H, aromatic in meta position toF; 6.98-7.08 sc, 2H, aromatic in ortho position to F; 6.20 dd, J=3.0 Hz,J′=4.3 Hz, 1H, CH═C; 4.48 t, J=3.0 Hz, 1H, CHCOOCH₃; 4.28 dt, J=18.6 Hz,J′=3.0 Hz, 1H, CH _(a)H_(b)N; 4.02 ddd, J=18.6 Hz, J′=4.2 Hz, J″=3.0 Hz,1H, CH_(a) H _(b)N; 3.64 s, 3H, COOCH ₃; 3.09 s, 3H, NCH ₃.

¹³C NMR (CDCl₃), δ (ppm): 168.7 COOCH₃; 162.1 d, J=247.2 Hz, Car-F;163.2 NCO; 132.9 Car in para position to F; 131.7 CH═C; 126.9 d, J=7.7Hz, CHar in meta position to F; 119.5 CH═C; 115.2 d, J=20.8 Hz, CHar inortho position to F; 52.7 COOCH₃; 51.8 CHCOOCH₃; 50.5 CH₂; 34.1 N—CH₃.

EXAMPLE 5 Mixture of4-(p-fluorophenyl)-1-methyl-2-oxo-1,2,3,6-tetrahydropiridine-3-carboxilicacid, methyl ester (IX, R: CH₃) and4-(p-fluorophenyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropiridine-3-carboxilicacid, methyl ester (IX′, R:CH₃)

To a solution of 10.3 g (0.037 mole) of compound VIII in 10 mL of MeOHwere added 10.4 mL of 21% MeONa (0.037 mole) for 1 hour at roomtemperature. After stirring for further 1 hour 2.3 mL of glacial AcOHwere added. The mixture was stirred for 1.5 hours at room temperatureand the solvent was removed under reduced pressure. 20 mL of CH₂Cl₂ and20 mL of water were added. The mixture was decanted and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were washedwith water and dried over. Na₂SO₄. The mixture was filtered and thesolvent was removed under reduced pressure, giving 8.73 g (90%) of asolid consisting of a 1:1 mixture of compounds IX and IX′.

EXAMPLE 6 (±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine(I)

To a stirred and cooled (0° C.) suspension of 2.12 g of lithiumaluminium hydride in 30 mL of anhydrous THF under nitrogen atmosphere,2.047 g (0.078 mole) of compound IX dissolved in 15 mL of anhydrous THFwere added. The mixture was heated at reflux for 3.5 hours and thentaken to 0° C. Successively, 2.12 mL of water, 2.12 mL of 5N NaOH and6.36 mL of water were slowly added. The precipitate was stirred for 1hour at room temperature, filtered and washed with THF. The filtrate wasdried over Na₂SO₄ and filtered and the solvent was removed under reducedpressure, yielding an oil which was crystallized with heptane. Afterfiltering and washing with heptane, the solid formed was recrystallizedfrom heptane, to give 1.13 g (65%) of compound I.

M.p.=122-124° C.

IR (KBr), cm⁻¹: 3170, 2937, 2794, 1603, 151, 1466, 1223, 1064, 831, 791.

¹H NMR (CDCl₃), δ (ppm): 7.18-7.08 sc, 2H, aromatic in meta position toF; 7.01-6.90 sc, 2H, aromatic in ortho to F; 4.10 sa, 1H, OH; 3.66 dd,J=10.5 Hz, J′=3.0 Hz, 1H; 3.22 m, 1H; 3.10 dd, J=10.5 Hz, J=7.8 Hz, 1H;2.89 m, 1H; 2.26 s, 3H, NCH ₃; 2.26-2.18 m, 1H; 2.06-1.66 sc, 5H;

¹³C NMR (CDCl₃), δ (ppm): 161.1 d, J=242.8 Hz, Car-F; 139.6 d, J=3.2 Hz,CHar in meta position to F; 115.1 d, J=20.9, CHar in ortho position toF; 63.1 CH₂OH; 59.5 CH₂; 56.0 CH₂; 46.3 CH₃; 44.3 CH; 43.6 CH; 34.2CH₂CH₂N.

1. A process for preparing(±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine of formulaI

which process comprises the reduction of a compound of the formula IX orIX′ or a mixture thereof

wherein R is an alky) group having 1 to 4 carbon atoms.
 2. The processas claimed in claim 1, wherein the reduction is performed with a hydrideor borane in a low-polarity solvent.
 3. The process as claimed in claim2, wherein the hydride is lithium aluminium hydride.
 4. The process asclaimed in claim 2, wherein the low-polarity solvent is selected fromtetrahydrofuran, ethyl ether, tert.-butyl methyl ether and mixturesthereof, and mixtures of at least one of the aforementioned solventswith toluene and/or an alkane and/or a cycloalkane.
 5. The process asclaimed in claim 4, wherein the low-polarity solvent is tetrahydrofuran.6. A compound of formula IX or IX′

wherein R is an alkyl group having 1 to 4 carbon atoms.
 7. A process forpreparing a compound of formula IX or IX′ or a mixture thereof,

wherein R is an alkyl group having 1 to 4 carbon atoms, which processcomprises the intramolecular condensation of a compound of formula VIII

wherein R is an alkyl group having 1 to 4 carbon atoms.
 8. A compound offormula VIII

wherein R is an alkyl group having 1 to 4 carbon atoms.
 9. A process forpreparing compound of formula VIII

wherein R is an alkyl group having 1 to 4 carbon atoms, which processcomprises the reaction of a compound of the formula VII

or an inorganic or organic acid addition salt thereof with an alkyl3-halo-3-oxopropionate of formula VII′XCOCH₂COOR  VII′ wherein X is chlorine or bromine and R is an alkylgroup having 1 to 4 carbon atoms.
 10. A compound of formula VII

or an inorganic or organic acid addition salt thereof.
 11. The compoundaccording to claim 10, wherein the inorganic acid addition salt is thehydrochloride.
 12. A process for preparing a compound of formula VII

or an inorganic or organic acid addition salt thereof, wherein theinorganic acid addition salt is the hydrochloride which processcomprises the hydrogenation of a compound of the formula VI

or of an addition salt thereof with an inorganic or organic acid in apolar solvent.
 13. The process according to claim 12, wherein the polarsolvent is selected from alkanols having 1 to 4 carbon atoms, water andmixtures thereof.
 14. The process according to claim 13, wherein thepolar solvent is a mixture of an alkanol having 1 to 4 carbon atoms andwater.
 15. A compound of formula VI

or an inorganic or organic acid addition salt thereof.
 16. The compoundaccording to claim 15, wherein the acid addition salts is thehydrochloride.
 17. A process for preparing(±)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine of formulaI

which process comprises i) reacting p-fluoroacetophenone withformaldehyde and methylbenzylamine or an addition salt thereof with atleast one inorganic or organic acid to obtain a compound of formula VI

 or an addition salt thereof with at least one inorganic or organicacid, ii) hydrogenating the compound of formula VI or the addition saltthereof to obtain a compound of the formula VII

 or an addition salt thereof, iii) reacting the compound of formula VIIor the addition salt thereof with an alkyl 3-halo-3-oxopropionate offormula VII′XCOCH₂COOR  VII′  wherein X is chlorine or bromine and R is an alkylgroup having 1 to 4 carbon atoms to obtain a compound of formula VIII,

 wherein R is defined as above, iv) performing an intramolecularcondensation of the compound of formula VIII to obtain a compound offormula IX or IX′

 wherein R is as defined above, or a mixture thereof, and v) reducingthe compound(s) IX and/or IX′ to obtain the compound of formula I. 18.The compound of claim 6, wherein the compound is formula IX.
 19. Thecompound of claim 6, wherein the compound is formula IX′.
 20. Acomposition comprising a mixture of compounds of formula IX and IX′

wherein R is an alkyl group having 1 to 4 carbon atoms.